The Farming and Movement Evaluation Study (FAME) is a case-control study of PD nested in the Agricultural Health Study (AHS);the latter is a cohort study of 89,000 licensed pesticide applicators and spouses designed to evaluate the role of farming-related exposures in chronic disease. The specific aims of FAME are to examine the relationship of PD to (i) pesticide exposure;(ii) other neurotoxicants, particularly metals;(iii) lifestyle factors including diet, smoking, and caffeine;(iv) skin melanin, to examine racial/ethnic differences;and (v) polymorphisms in genes involved in dopaminergic neurotransmission, xenobiotic metabolism, or xenobiotic-specific membrane transport. Field work for the case-control study is complete;115 cases and 384 controls were enrolled. Suspect cases were identified using information from the AHS, and the diagnosis of PD was verified by movement disorder specialists using an in-home neurologic exam, a videotaped movement evaluation, and medical records including response to medication. Controls were a random sample from the remaining cohort, frequency matched to cases by age, sex, and state. Exposure was evaluated using data from three complementary sources: (i) interview information on pesticide use, other exposures, and lifestyle already collected in the AHS;(ii) blood samples to measure organochlorines and metals and for DNA banking;and (iii) new telephone interviews which obtained information on specific pesticides implicated in PD as well as exposure to other neurotoxicants. The major paper from this study confirming association of PD with pesticide exposure is complete. Our goal for this analysis was to determine whether pesticides that cause mitochondrial dysfunction or oxidative stress -- pathophysiologic mechanisms implicated in PD by experimental models and genetic forms of PD -- are associated with PD or clinical features of parkinsonism in humans. We assessed lifetime use of pesticides selected by mechanism. We found that PD was associated with use of a group of pesticides that inhibit mitochondrial complex I odds ratio (OR) = 1.7;95% confidence interval (CI), 1.02.8 including rotenone (OR = 2.5;95% CI, 1.34.7) and with use of a group of pesticides that cause oxidative stress (OR = 2.0;95% CI, 1.23.6), including paraquat (OR = 2.5;95% CI, 1.44.7). Thus, PD was positively associated with two groups of pesticides defined by mechanisms implicated experimentally, supporting a role for these mechanisms in PD pathophysiology. We investigated the relationship of blood metal levels to PD by measuring whole blood metal levels using inductively coupled plasma-mass spectrometry. For cases, the mean time between diagnosis and blood collection was 7.4 years. Seven of ten elements analyzed were detected in almost all subjects (copper, iron, lead, magnesium, manganese, selenium, and zinc). While we saw expected associations of metals with known predictors (eg, lead and smoking, lead and age), we observed no differences in blood metal levels between cases and controls, nor did we find differences related to time since diagnosis among cases. The half-life of metals in blood is relatively short, and the latency between metal exposure and disease may be long. Thus measuring current blood levels may not reflect the etiologically relevant time-window. We have also conducted studies of genetic susceptibility. We evaluated the role of common polymorphic variants in SNCA, the gene for synuclein, a protein important in some cases of familial PD. Genetic variability in SNCA has been inconsistently associated with sporadic PD risk. We evaluated 61 SNCA variants in FAME, selected based on prior association, population frequency, and mechanistic hypotheses. Three SNPs deviating from HWE and with poor call rates were excluded from analysis. Four SNPs were mono-allelic. Call rates were >0.98 for all others. Seven SNPs were associated with PD risk (P<0.10), three directly and four inversely. Haplotypic analyses did not identify stronger associations. We conclude that common SNCA SNPs are associated with PD, although none was significant after Bonferroni correction. Our observations replicate prior reports for rs356186, rs3822086, rs2737026, and rs2736994. Other associations are either novel or conflict with prior reports. These results further support SNCA as a susceptibility locus for PD, but suggest significant population heterogeneity or environmental interaction. We investigated the hypothesis that variability in SNCA Rep1, a polymorphic dinucleotide microsatellite in the promoter region of the alpha-synuclein gene, modifies the association between head injury and PD risk. Participants in FAME and SEARCH, a second case-control study, were genotyped for Rep1 and interviewed regarding head injuries with loss of consciousness or concussion prior to PD diagnosis. Relative to medium-length Rep1, short Rep1 genotype was associated with reduced PD risk (OR 0.7, 95% CI 0.5-0.9), and long Rep1 with increased risk (OR 1.4, 95%CI 0.95-2.2). Overall, head injury was not significantly associated with PD (pooled OR 1.3, 95%CI 0.9-1.8). However, head injury was strongly associated with PD in those with long Rep1 (FAME OR 5.4, 95%CI 1.5-19;SEARCH OR 2.3, 95%CI 0.6-9.2;pooled OR 3.5, 95%CI 1.4-9.2, p-interaction 0.02). Individuals with both head injury and long Rep1 were diagnosed 4.9 years earlier than those with neither risk factor (p = 0.03). Thus, while head injury alone was not associated with PD risk, our data suggest head injury may initiate and/or accelerate neurodegeneration when levels of synuclein are high, as in those with Rep1 expansion. Two other genetic analyses used data from a consortium of five North American case-control studies. The dopamine receptor D2 (DRD2) and D3 (DRD3) genes are associated with both PD risk and nicotine dependence. In an analysis including 1325 PD cases and 1735 age- and sex-matched controls, we evaluated whether polymorphisms in these genes were associated with PD risk or modified the inverse association of smoking with PD. Six DRD2 and two DRD3 polymorphisms were genotyped in a single laboratory. Smoking data were collected with a structured interview. Among white non-Hispanics, homozygous carriers of the Taq1A DRD2 variant had increased PD risk compared to wildtype homozygotes (OR=1.5, 95% CI 1.0-2.3). In contrast, there was an inverse association of PD risk with the Taq1A variant in African Americans. Among white Hispanics who carried two alleles, the Ser9Gly DRD3 variant was associated with a decreased risk of PD (OR=0.4, 95%CI 0.2-0.8). The inverse association of smoking with PD risk was not modified by any of the DRD2 or DRD3 polymorphisms. In animal models of PD, caffeine neuroprotection involves blocking the adenosine receptor A2A (ADORA2A). Cytochrome P450 1A2 (CYP1A2) is the primary pathway of caffeine metabolism. In an analysis of 1325 PD cases and 1735 controls, we evaluated whether ADORA2A and CYP1A2 polymorphisms were associated with PD or modified the inverse association of caffeine with PD. Information on caffeine intake was collected by structured interview. Four ADORA2A and four CYP1A2 polymorphisms were genotyped in a common laboratory. Two ADORA2A polymorphisms were inversely associated with PD risk, ss993074955, a 5 variant (allelic OR= 0.51, 95% CI 0.33-0.80) and rs5996696, a promoter region variant (ORs for AC and CC genotypes compared with the AA genotype were 0.76 (95% CI 0.57-1.02) and 0.37 (95% CI 0.13-1.01), respectively). Other ADORA2A and CYP1A2 polymorphisms were not associated with PD. There was no genotype X caffeine interaction for ADORA2A polymorphisms. For CYP1A2, the caffeine-PD association was strongest among subjects homozygous for variant allele for rs762551 and rs2470890 (p for interaction <0.10).